Prostaglandin E2 (PGE2) is a major mediator of inflammation. Acutely, PGE2 favors a pro-inflammatory immune response; but, sustained levels in tumor microenvironment promote the accumulation and enhance the activity of multiple immunosuppressor cells, including tumor associated macrophages (TAM), Treg cells, and myeloid-derived suppressor cells (MDSCs), and consequently promote tumor immune escape (Kaidi A, et al. Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia. Cancer Res, 2006, 66:6683-6691; Nakanishi Y et al. COX-2 inhibition alters the phenotype of tumor-associated macrophages from M2 to M1 in APCmin/+ mouse polyps. Carcinogenesis, 2011, 32:1333-1339; Mahic M et al. FOXP3+CD4+CD25+ adaptive regulatory T cells express cyclooxygenase-2 and suppress effector T cells by a prostaglandin E2-dependent mechanism. J Immunol, 2011, 177:246-254; Adams J L et al. Big opportunities for small molecules in immune-oncology. Nat Rev Drug Disc, 2015, dol:10.1038/nrd4596).
Signaling of PGE2 is mediated by a set of four EP receptors (EP1, EP2, EP3 and EP4), which are coupled to different signal transduction pathways in different cell lineages. Accumulating evidence has demonstrated that elevated cAMP levels through EP4 are the primary signal leading to immunosuppression in immune cells (Yokoyama U et al. The prostanoid EP4 receptor and its signaling pathway. Pharmacol Rev, 2013, 65:1010-1052). Knockout of EP4 in mice showed delayed tumorigenesis compared to wild-type animals in the background of APCmin mutation, indicating a tumor-promoting activity of PGE2-EP4 signaling in host immune cells (Mutoh M et al. Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis. Cancer Res, 2002, 62:28-32). Consistently, selective EP4 receptor antagonists have been shown to slow tumor progression in various preclinical tumor models without affecting the cancer cell proliferation in vitro (Yang et al. Host and direct anti-tumor effects of profound reduction in tumor metastasis with selective EP4 receptor antagonism. Cancer Res, 2006, 66:9665-9672; Mao Y et al. Inhibition of tumor-derived prostaglandin e2-blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activity. Clin Cancer Res, 2014, 20:4096-4106).
These results suggest that suppression of PGE2/EP4 signaling may have therapeutic value in cancer and other chronically inflammatory diseases such as multiple sclerosis and rheumatoid arthritis. Hence, there is a need for novel compounds capable of suppressing PGE2/EP4 signalling.